Methods for making immobilized aryl-containing ligands

ABSTRACT

Organic ligands that contain at least one aryl group are immobilized on a solid support. The organic ligands are of the type used to form a catalyst complex suitable for carrying out a catalytic reaction, preferably an asymmetric reaction. To immobilize the organic ligands, a tethering group is bonded to the ligand using, for example, a Friedel-Crafts acylation or alkylation reaction. The immobilization of the organic ligand can be carried out using a single reaction with the organic ligand.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/838,067, filed Aug. 13, 2007, the disclosure of which is incorporatedherein in its entirety.

BACKGROUND OF THE INVENTION

1. The Field of the Invention

The present invention relates to methods for immobilizingaryl-containing organic ligands on a support material. The organicligands are immobilized using a tethering agent that is bonded to thearyl group and to a support material.

2. The Relevant Technology

Catalysts are widely used in the manufacturing of organic compounds suchas pharmaceuticals, agrochemicals, flavors, fragrances, and otherfunctional materials. Catalysts can be generally divided into two maintypes, homogeneous and heterogeneous. Homogeneous catalysts arecatalysts which are in the same phase as the reactants and/or productsduring the chemical reaction. Heterogeneous catalysts are catalysts thatare not in the same phase as the reactants and/or products during thechemical reaction.

Homogeneous reactions are typically carried out in a liquid solutionwith a catalyst that is soluble in a liquid reaction medium. A catalystdissolved in liquid phase reactants and products can be advantageous forachieving good selectivity and activity. In contrast, heterogeneousreactions are typically carried out in a liquid reaction medium, but theheterogeneous catalyst is typically in a solid phase. Heterogeneouscatalysts can be separated from the liquid phase using separationtechniques such as filtration or centrifugation.

Homogeneous catalysts are important in the pharmaceutical and finechemicals industries where there is a growing need for catalysts thatmeet special selectivity requirements. Recently there has been anincreased need for chiral selectivity to produce single enantiomerproducts. The need for single enantiomers is particularly important forpharmaceuticals where one enantiomer may have a beneficialpharmacological effect and another enantiomer of the same compound mayhave an undesirable side effect. Even when one enantiomer is not knownto cause adverse affects, manufacturing a single enantiomer can beadvantageous to simply avoid the expense of clinical trials on bothenantiomers.

Historically, homogeneous catalysts, especially soluble organometalliccomplexes (metal-ligand complexes), have proven to be the most effectivein achieving chiral selectivity. The challenge with using homogeneouscatalysts is to remove the catalyst from the final product. Catalyststhat are soluble in the same phase as the product can be difficult toseparate from the product since the two species will be intimatelymixed. Homogeneous catalysts that remain in the final product are oftena source of contamination and reduce the quality of the final product.On the other hand, simply attaching a homogeneous catalyst to a supportis not feasible, as it may de-activate the catalyst or interfere withthe desired catalytic activity (e.g., by altering a desired conformationof the ligand as a result of a portion of the ligand being bound orattached to the solid support, and/or as a result of steric hindrance).

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to methods for immobilizing anaryl-containing organic ligand to a support using an organic tetheringagent. The methods of the invention are carried out so as to reduce orminimize the number of reaction steps needed to immobilize the organicligand, thereby improving the yield of immobilized organic ligand. Thetethering agent used to immobilize the organic ligand to the supportmaterial is a bifunctional or polyfunctional organic compound. Thetethering agent includes a functional group near one end for bonding tothe organic ligand (a “bonding functional group”) and another functionalgroup near another end for bonding the tethering agent to a support (an“anchoring functional group”).

In one embodiment of the invention, the bonding functional group and theanchoring functional group are selected such that the reaction betweenthe bonding functional group and the organic ligand can be carried outin the same reaction medium as the reaction between the anchoringfunctional group and the support. In a preferred embodiment, the tworeactions are carried out simultaneously. Selecting a tethering agentthat can be reacted with the support material and the organic ligand inthe same reaction results in high yields of the immobilized organicligands from a given amount of ligand as starting reagent.

In one embodiment, the tethering agent is bonded directly to the arylgroup through a carbon-carbon coupling reaction. In a preferredembodiment, the bonding group is reacted with the aryl group of theorganic ligand using a Freidel-Crafts acylation or alkylation reaction.The Freidel-Crafts acylation or alkylation reactions allow the ligand tobe immobilized in a single step thereby giving high yields for theimmobilization reaction. In addition, the carbon-carbon bond between thetethering group and the aryl group minimizes the effect that thetethering group has on the aryl group.

The type of bonding functional group on the tethering agent will dependon the particular organic ligand being immobilized. Examples of suitablebonding functional groups include hydroxyl groups, carboxyl groups, acylhalide groups, olefinic groups, and the like. In a preferred embodiment,the bonding functional group is an alkyl or acyl halide that can bedirectly bonded to the aryl group of the organic ligand. The bondingbetween the tethering agent and the ligand will be sufficiently strongto provide a useful degree of attachment, yet will not excessivelymodify the chemical environment of the organic ligand, therebypreserving the catalytic function and activity of a catalystincorporating the ligand. Bonding the tethering agent to a ligand ratherthan the metal center has been found to minimize the effects that thetethering agent has on catalytic function.

In one embodiment the organic ligand is useful for forming anorganometallic complex and/or is useful for making catalysts that aretypically used as homogeneous catalysts. The present invention isparticularly useful for immobilizing organometallic complexes that areuseful for asymmetric syntheses, and exhibit high chiral selectivity.Immobilizing chiral catalyst according to the methods of the presentinvention can be advantageous because of the high cost of chiralcatalysts and the difficulty of immobilizing chiral catalysts withoutsignificantly compromising catalytic activity. Because chiral catalystsare highly susceptible to steric hindrances, the tethering agents of thepresent invention can be used to immobilize chiral catalysts that wouldotherwise be rendered inactive using conventional immobilizationtechniques.

The anchoring functional group is selected to react with availablefunctional groups on the surface of the support or functional groupsavailable through an extender group that is bonded to the surface of thesupport. Examples of anchoring functional groups suitable for bonding tothe support (i.e., the surface of the support or an extender bonded tothe surface of the support) include hydroxyl, carboxyl, acid halide,nitrile, pyridine, amine, carbonyl, sulfate, SO₃, PO₅, alkylchlorosulfite, and other reactive groups containing oxygen, nitrogen,sulfur, or phosphorus.

The solid support can be any support that has functional groups or canbe modified to have functional groups for bonding the tethering agentand/or an extender group. Examples of suitable supports include solidoxides, inorganic carbons, polymers and resins, natural and syntheticzeolites, and natural minerals such as clays and the like. The solidsupport can be functionalized to have any functional group desired forreacting with the tethering agent. Examples of suitable functionalgroups include hydroxyl, carboxyl, acid halide, nitrile, pyridine,amine, carbonyl, sulfate, SO₃, PO₅, alkyl chlorosulfite, aromatic groupssuch as benzyl groups, and other reactive groups containing carbon,oxygen, nitrogen, sulfur, and/or phosphorus.

The extender is an organic molecule that can add chain length to thetethering agent to provide added separation between the support and thecatalytic complex. The use of an extender is particularly advantageousto achieve long chain lengths while avoiding tethering agents with poorsolubility. The extender can be any organic agent that can react on oneend with the tethering agent and react with the support on another end.The extender can be reacted with the support and the tethering agent inany order or simultaneously. Examples of suitable extenders includethose agents listed above with respect to tethering agents or otheragents such as silanes.

The organic ligands are typically reacted with metals and/or otherligands to form a catalyst, including organometallic complexes. Theligands give the catalyst complexes certain catalytic properties, whichare maintained in part by spacing the catalyst complex from the supportsurface. In a preferred embodiment, the tethering agent, and theoptional extender agent, spaces the organic ligand from the supportmaterial by a main chain of at least 5 atoms, more preferably at least 8atoms, even more preferably at least 10 atoms, and most preferably atleast 12 atoms. For chain lengths greater than 10, the use of anextender may be advantageous to maintain solubility of the tetheringagent. When the ligand is complexed to form a catalyst, the spacingbetween the ligand and the support material allows the immobilizedcatalyst to be accessible to molecules in a gas or liquid phase, therebyallowing reactants to reach the catalytic active sites of the complex.The spacing also minimizes the interference that the support might havewith catalyst complexes.

The immobilization to the solid support allows the catalyst complexesemploying the organic ligand to be recovered from the reaction productusing techniques not available for separating a homogeneous catalyst.The immobilized ligands and/or catalyst complexes of the invention canbe separated from the reaction product and residual reactants using anytechnique that will separate a solid support from a liquid including,but not limited to, filtration, centrifugation, and/or screening. Theseseparation techniques allow the heterogeneous catalysts to achieve along useful life in a continuous process or to be used in a batchprocess where the catalyst is recovered and recycled numerous times.

The immobilized catalyst complexes of the invention have a chemicalstructure and behavior that is substantially similar to the structureand behavior of the analogous non-immobilized complex in the homogeneousstate. The immobilized catalyst complexes of the invention combine theadvantages of homogeneous catalysts (high activity and selectivity,including chiral selectivity) with the advantages of heterogeneouscatalysts (simple catalyst recovery and long catalyst life). The bondingto the support minimizes metal leaching during the catalytic organicreaction, even under varied conditions. In addition, the relatively longchain length separating the support from the catalyst complex ensuresthat the catalyst complex has freedom to move about in the solution,thereby avoiding changes to the electronic and steric environment aroundthe active center and maintaining high activity and selectivity.

These and other advantages and features of the present invention willbecome more fully apparent from the following description and appendedclaims.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

The present invention relates to immobilized organic ligands thatcontain at least one aryl group. The organic ligands can be used to forma catalyst complex suitable for carrying out a catalytic reaction,preferably an asymmetric reaction. To immobilize the organic ligands, atethering group is bonded to the ligand using, for example, aFriedel-Crafts acylation or alkylation reaction. The tethering agent isalso bonded to the support material either directly or through anextender agent. The tethering group is selected to minimize number ofreaction steps needed to immobilize the organic ligand, while minimizingthe effect that the tethering group and/or support has on catalyticactivity. The following description describes the immobilization of anorganic ligand that is part of an organometallic complex. Those skilledin the art will recognize that the invention can be carried out bysimply immobilizing a ligand that is useful for forming a catalystcomplex. Therefore, while the following description describes theinvention in the context of a catalyst complex, the present inventionincludes organic ligands that are immobilized on a support material andthat are useful for thereafter forming an immobilized catalyst complex.

I. Components Used to Make Immobilized Complexes

The catalysts of the invention are manufactured from a catalyst complex,a tethering agent, a support material, optionally one or more solvents,and optionally an extender.

A. Catalyst Complexes

The catalyst complexes include a plurality of organic ligands. At leastone of the organic ligands includes an aryl group. Examples of suitablearyl groups include aryl, aryl-O, and/or aryl-N (without any electronwithdrawing substituents such as —NO₂, —CN, —COOH, etc). Examples ofaryl groups suitable for bonding with the tethering agent includebenzene, indene, naphthalene, fluorine, chrysene, phenanthrene,anthracene, triphenylene, and their aryl-O and aryl-N derivatives.

Preferably the aryl group of the organic ligand is unmodified from itsstructure as used in a homogenous catalyst, or in other words the arylgroup is not functionalized. In this embodiment, the tethering agent isreacted directly with the aromatic ring using, for example, aFreidel-Crafts or Suzuki reaction. In a preferred embodiment, thereaction forms a carbon-carbon bond with the aryl group. In analternative embodiment, the invention can be carried out on an organicligand that has been functionalized so as to have a desired functionalgroup that can then be reacted with the tethering agent. In thisembodiment, the additional step to functionalize the aryl group iscarried out to provide a functional group more suitable for carrying outa single step reaction with the tethering agent. The use of an organicligand with a functionalized aryl group can be useful where thefunctionalization allows for a single step immobilization reaction ofparticularly high yields. Examples of suitable functionalization for thearyl group include hydroxyl groups, carboxyl groups, olefinic groups,and the like.

In one embodiment, one or more of the organic ligands includesphosphorus. Preferably the one or more organic ligands impart chiralityto the catalyst complex such that the catalyst complex is useful forcarrying out asymmetric reactions. Examples of suitable chiralphosphorous compounds include but are not limited to altropisomericbiaryl bisphosphine compounds, bisphosphane compounds, and their alkyl,alkyl-O, and alkyl-N substituted derivates (except derivativessubstituted with electron withdrawing groups). Specific examples ofsuitable chiral phosphorous ligand systems include, but are not limitedto the following:

The catalyst complex optionally includes a metal center that providesthe catalytic active center. The metal component can be any metalsuitable for making an organometallic complex. Examples of suitablemetals include the platinum group metals and base transition metals.Precious metals are preferred for many pharmaceutical catalysts and forasymmetric synthesis. If the organometallic complex is to bemanufactured during the immobilization procedure (i.e., theorganometallic complex is not provided as an already prepared complex),the metal is typically provided as a metal salt or other metal compoundsuitable for reacting the metal with the one or more ligands to make thecatalyst complex.

Those skilled in the art are familiar with the various asymmetricreactions that can be carried out using organometallic complexes havingone or more of the foregoing ligands. In one embodiment, the organicligands and catalyst complexes can be of the type useful, at least inpart, for carrying out asymmetric hydrogenation, asymmetric epoxidation,asymmetric dihydroxylation, asymmetric Diels-Alder reaction, or similarasymmetric reactions.

Examples of specific suitable catalyst complexes include Rh-DIPAMP,which can be used to manufacture _(L)-DOPA, an important drug used totreat Parkinson's disease. In another embodiment, ruthenium, rhodium, orpalladium complexed with BINAP can be used for asymmetric hydrogenationto make novel olefins.

B. Tethering Agents and Extenders

The catalyst complexes are immobilized using a tethering agent. Thetethering agent is a bifunctional or polyfunctional molecule capable ofproviding strong bonding between the aryl group of the organic ligandand the support. The tethering agent includes at least two functionalgroups, one of which can serve as a bonding functional for bonding thetethering agent to the organic ligand and the other which can serve asan anchoring functional group for bonding the tethering group to thesupport material (i.e., the support surface or an extender agent bondedto the support surface).

The bonding functional groups and the anchoring functional groups can bethe same or different. In a preferred embodiment, the anchoring groupsand the bonding groups are selected such that they can be reacted withthe support and the ligand, respectively, under the same reactionconditions.

Examples of suitable anchoring functional groups and bonding functionalgroups include alkyl halide, acyl halide, hydroxyl, carboxyl, acidhalide, nitrile, pyridine, amine, carbonyl, sulfate, SO₃, PO₅, alkylchlorosulfite, and other reactive groups containing carbon, oxygen,nitrogen, sulfur, and/or phosphorus. In principle, the tethering agentmay have any of these functional groups, singly or in combination, solong as each tethering agent molecule has at least one functional groupthat can bond with the organic ligand of the organometallic complex andanother functional group that can be anchored to a solid support.

Examples of suitable tethering agents include, but are not limited to(i) acyl halides such as acyl chlorides containing additional activefunctional groups, including hydroxy acyl chlorides, such as compoundsof the general formula HO(CH_(x))_(n)COCl, and carboxy acyl chlorides,such as compounds of the general formula HOOC(CH_(x))_(n)COCl, anddiacyl chlorides, such as compounds of the general formulaClOC(CH_(x))_(n)COCl, or bromides of any of the forgoing; (ii) alkylhalides including, but are not limited to (i) acyl chlorides containingadditional active functional groups, including hydroxy alkyl chlorides,such as compounds of the general formula HO(CH_(x))_(n)CCl, and carboxyalkyl chlorides, such as compounds of the general formulaHOOC(CH_(x))_(n)CCl, and dialkyl chlorides, such as compounds of thegeneral formula ClOC(CH_(x))_(n)CCl, or bromides of any of the forgoing.

Optionally, an extender agent can be used to add additional chain lengthto the tethering agent. The extender molecules are selected to bond withthe tethering agent and the support material. The extender agent can beany organic molecule that has functional groups capable of bonding tothe support and to the tethering agent. Examples of suitable extenderagents include (i) polyfunctional carboxylic acids, including diacidssuch as oxalic acid, malonic acid, succinic acid, glutaric acid, adipicacid, maleic acid, fumaric acid, phthalic acid, isophthalic acid,terephthalic acid, and the like; polyacids with functionality of threeor greater, including citric acid and the like, as well as polymericacids such as polyacrylic acid and the like; (ii) hydroxy acids such asglycolic acid, salicylic acid, hydroxy propanoic acid, and the like;(iii) acyl halides such as acyl chlorides containing additional activefunctional groups, including hydroxy acyl chlorides, such as compoundsof the general formula HO(CH_(x))_(n)COCl, and carboxy acyl chlorides,such as compounds of the general formula HOOC(CH_(x))_(n)COCl, anddiacyl chlorides, such as compounds of the general formulaClOC(CH_(x))_(n)COCl; (iv) nitriles, particularly those that containboth one or more nitrile groups along with at least one other group suchas hydroxyl, carboxyl, or acyl chloride, including hydroxyacetonitrile,3-hydroxyproprionitrile, 2-hydroxyisobutyronitrile, carboxyacetonitrile,and the like; and (v) pyridines, such as those that contain both one ormore pyridine groups along with at least one other group such ashydroxyl, carboxyl, or acyl chloride, including 2-hydroxymethylpyridine,picolinic acid (2-pyridine carboxylic acid), nicotinic acid (3-pyridinecarboxylic acid), and/or quinolinic acid (2,3-pyridine dicarboxylicacid). The functional groups on the tethering agent and the extenderagent are selected so as to ensure that the extender agent bonds to thesupport and the tethering agent bonds to the extender so as to form adesired chain length separating the organometallic complex from thesupport.

C. Solid Support

A variety of solid support materials may be used for the presentinvention, including various solid oxides (alumina, silica, zirconia,titania, ceria, and the like), inorganic carbons (carbon black,activated carbon, graphite, and the like), polymers and resins, naturaland synthetic zeolites, and natural minerals such as clays and the like.The solid supports have surface functionalities that can be used asanchoring sites for the tethering agents and/or extender agents of thepresent invention. Example functionalities include hydroxyl, sulfonate,amine, and aromatic groups such as benzyl groups. The solid support canbe provided in a variety of physical forms, including powder, pellets,spheres, extrudates, or the like. One suitable support is a reversephase silica with aromatic functionalities on its surface.

D. Solvents

The immobilized catalyst complexes of the invention are typicallymanufactured using a solvent. Any solvent can be used so long as it issuitable for the particular reaction performed to make the catalyst. Forexample, when carrying out the Freidel-Crafts reaction, the solvent istypically nitrobenzene. In the case where a solid support isfunctionalized with an extender agent, other solvents can be used,including toluene, water, alcohols such as methanol and ethanol, and avariety of other common organic solvents, and their mixtures. Thepreferred choice of solvent will depend on several factors, such as thesolubility of the starting materials. Where more hydrophilic solventsare desired, the immobilized catalyst can be manufactured using anextender such that longer chain lengths can be achieved while usingagents with higher solubility in common solvents.

II. Methods for Manufacturing Immobilized Catalysts

The present invention also provides methods for producing immobilizedorganic ligands and immobilized catalyst complexes. The immobilizedorganic ligands and catalyst complexes are manufactured by firstselecting a particular organic ligand or catalyst complex to beimmobilized and then selecting the proper components to immobilize theligand or complex. The particular tethering agent, solvents, solidsupport, and optionally extender agents are selected according to thesolubility of the ligand or complex, the solubility of the tetheringagent and/or the extender agent, the available functional groups on thesurface of the solid support, and the yields that the reactions willproduce.

The immobilized organic ligands and/or catalyst complexes can bemanufactured using several different synthesis routs. In one embodiment,the method includes (i) providing an organic ligand comprising at leastone aryl group or a functionalized aryl group; (ii) providing a supportmaterial having a plurality of available functional groups; (iii)providing a tethering agent having an anchoring functional group capableof bonding with the support material and a bonding functional group thatis capable of bonding to the aryl group or the functionalized arylgroup, wherein the anchoring functional group is selected so as to becapable of reacting with the support material in the same reactionmedium as a reaction medium used to react the bonding functional groupwith the aryl group or the functionalized aryl group; and (iv) in asingle reaction medium, (1) reacting the bonding group of the tetheringagent with the aryl group or functionalized aryl group and (2) reactingthe bonding group of the tethering agent with the support material, soas to yield an aryl-containing organic ligand immobilized on the supportmaterial.

In an alternative embodiment, the method includes the steps of (i)providing an organic ligand that includes at least one aryl group, (ii)reacting the tethering agent with the organic ligand using a FreidelCrafts acylation or alkylation reaction or other reaction suitable forforming a carbon-carbon bond with the aryl group, and (iii) reacting thetethering agent with the support material.

The reaction between the tethering agent and the organic ligand can becarried out by mixing the tethering agent and the ligand or complex inan appropriate solvent under conditions that allow or cause thetethering agent to with the aryl group of the organic ligand and form acarbon-carbon bond. The tethering agent and organic ligand can bereacted using catalysts, mixing, heating, refluxing, reducing agents,and/or other suitable techniques. In a preferred embodiment, thetethering agent includes an alkyl halide group or an acyl halide groupand the organic ligand includes an aryl group that is available forbonding with the alkyl halide or acyl halide through a Freidel-Craftsalkylation or Freidel-Crafts-acylation reaction. Examples of suitablearyl groups that can be a component of the organic ligand and bonded tothe tethering agent through an alkylation reaction or an acylationreaction include, but are not limited to, indene, naphthalene, fluorine,chrysene, phenanthrene, anthracene, chrysene, and triphenylene. In oneembodiment, the organometallic complex includes at least two aryl groupsthat are bonded together and the tethering agent is bonded to one of thetwo conjoined aryl groups. The acylation reaction and the alkylationreaction can be carried out using conditions and catalysts known tothose skilled in the art.

The reaction involved in bonding the tethering agent to the support orthe extender agent will depend on the particular functional groupsavailable on the support or the extender agent. Generally, the tetheringagent and the support are mixed together in a solvent under conditionssuitable to the anchoring functional group of the tethering agent tobond with available functional groups on the surface of the support, oroptionally an available functional group on the extender agent. Forexample, in one embodiment, the tethering agent can include a silanethat is bonded to hydroxyl groups on the surface of an oxide material(e.g., silica or alumina). Similarly, the anchoring functional group ofthe tethering agent can be reacted with functional groups on theextender agent to form a strong bond (e.g., and ester or amide linkage).

In general, the solid support, extender agent, tethering agent, organicligand, and any other components of the immobilized catalyst complexescan be reacted in any order to form the proper linkages betweencomponents and/or to manufacture the organometallic complex, so long asthe reactions for each step are compatible with the components presentin the reaction mixture. In a preferred embodiment, the reaction orderis selected so as to minimize the number of reactions that involve theorganic ligand and/or so as to maximize the yield of immobilized organicligand for a given amount of ligand used as a starting reagent. Forexample, in one embodiment, the tethering agent can be reacted with thesupport prior to being reacted with the organic ligand. The tetheringagent can also be reacted with the organic ligand prior to or after theorganic ligand is bonded to the metal to form an organometallic complex.Similarly, the extender, is preferably reacted with the support beforeor simultaneously with being reacted with the tethering agent.

In a preferred embodiment, the organic ligand is immobilized to thesupport material in a single step reaction. The single step reaction canbe accomplished by selecting a tethering agent that can react with thearyl group and with the support or an extender group on the support in asingle reaction. In one embodiment, the tethering agent is a diacylhalide that is reacted with the aryl group of the tethering agent andthe support/extender in a single step reaction. For example, the supportmaterial can have aromatic functional groups on its surface such thatthe diacyl halide reacts with the aromatic group on the support and thearyl group of the organic ligand in a single reaction.

Another example of a single step reaction includes an inorganic supportmaterial that is treated with an amino silane extender group. The silanegroup reacts with the inorganic support (e.g., silica) and the amine isthen available for the single step reaction with a diacyl halide and theorganic ligand. Acylation or alkylation with a diacyl or dialkyl halidecan be carried out in a single reaction with one alkyl halide or acylhalide reacting with the amine group and the other alkyl halide or acylhalide reacting with the aryl group of the organic ligand. While thisembodiment includes more than one reaction step, the organic ligand isonly involved in one of the reaction steps to accomplish immobilization.

Imobilizing the organic ligand in a single step reaction can beadvantageous because it minimizes the loss of expensive ligand due toreaction yields. Although a single reaction step involving the organicligand is preferred, the invention can also be carried out using theorganic ligand in more than one step so long as the yields of themultiple steps are relatively high.

The immobilized ligands are typically used to form a catalytic complex.The catalytic complex can include a catalytic metal or a plurality ofadditional ligands that form a complex. The catalytic complex istypically manufactured using known techniques. The organic ligand can beconverted into the desired catalyst complex by reaction with appropriateligands at one of several points. For example, the an organometalliccomplex may be formed prior to the formation of the tetheringagent-organic ligand bond, such that a metal-ligand complex exists priorto reacting the ligand with the tethering agent molecules. Alternately,the various ligands can be reacted with a metal or other organic ligandsafter the tethering agent has been bonded to one of the ligands, suchthat the catalyst complex is formed in situ in the reaction mixture.

At the completion of any of the abovementioned methods, a driedimmobilized organic ligand and/or catalyst complex is obtained. Oncedried, the immobilized catalyst can be used as is. However, it may bepreferred in some cases to subject the material to further treatment toobtain the final immobilized catalyst. For example, various heattreatments can be used in various combinations, including any sequenceor combination of heating the material in inert, oxidizing, or reducingatmospheres. This treatment may cure or set the anchoring bond betweenthe tethering agent and the solid support, or may encourage somerequired chemical or structural modification of the material.

III. Immobilized Ligands

The immobilized organic ligands of the present invention are arylcontaining ligands that are bonded to a tethering group through acarbon-carbon bond and immobilized on a solid support material. Thetethering group provides spacing between the organic ligand and thesolid support. The separation between the organic ligand and the supportmaterial minimizes the adverse effects that the support can have on theactivity of the catalyst complex employing the organic ligand. Inaddition, bonding the tethering group to the ligand minimizes thechances that the tethering agent will adversely affect the electricalproperties of the active center of the catalyst complex.

The length of the main chain between the support and the aryl group isselected to provide a desired amount of spacing. In one embodiment, thetethering group, and optionally an extender group, together provide amain chain of at least 5 atoms. In a preferred embodiment, the mainchain is at least 8 atoms long, more preferably at least 10 atoms long,and most preferably at least 12 atoms long.

For purposes of this invention, the main chain of atoms are atoms thatare linked in a linear chain between the surface of the support and theligand of the organometallic complex. The main chain can be a straightchain of atoms or can form a portion of a cyclical compound. The mainchain can include heteroatoms, single bonds, double bonds, branching,and the like. In a preferred embodiment, the atoms of the main chain arebonded through single bonds so as to give the main chain the greatestdegree of freedom.

In one embodiment of the invention, the immobilized catalyst complexesof the invention have the following general structure:

In the foregoing structure, M is metal atom; Ar₁ and Ar₂ areindependently an aryl group, an aryl-O group, or an aryl-N group, withthe proviso that the group does not have an electron withdrawingsubstituent; R₂-R₆ are independently an alkyl group or an aryl group;and L₁ and L₂ are independently a halogen, an amine, or an amide.

In a preferred embodiment, R₁ and R₂ are an alkyl chain having 1-18carbon atoms and/or Ar₁ and Ar₂ are selected from the following group ofaryl compounds or their aryl-O or aryl-N derivatives:

In one embodiment, R₃-R₆ are an altropisomeric biaryl bisphosphinecompound or a bisphosphane compound such as, but not limited to, chiralBINAP, BICHEP, DIPAMP, BINAPHANE, BINAPO, BDPAB and their alkyl,alkyl-O, alkyl-N substituted derivates (with the proviso that thesubstituents do not include electron withdrawing groups). Examples ofsuitable compounds include the following:

IV. Methods of Use

The immobilized organic ligands or catalyst complexes of this inventionare useful for a wide variety of chemical reactions, includinghydrogenation, oxidation, dehydrogenation, coupling, and otherreactions. These catalysts are particularly advantageous for conductingreactions that would normally require purely homogeneous catalysts, suchas highly selective reactions for the production of valuable finechemicals and pharmaceutical ingredients, including asymmetric reactionsthat require chiral selectivity to produce single enantiomer products.

The immobilized catalyst complexes are typically used in reactions wherethe catalyst is in a solid phase and the reactants are in a liquidphase. Because the immobilized catalyst complexes are in a solid phaseand the reaction medium is in a liquid phase, it can be very easy toremove the heterogeneous catalyst from the reaction product. In oneembodiment, the catalysts are used to catalyze a reaction (e.g.,hydrogenation, oxidation, dehydrogenation, or coupling) and then thecatalyst is separated from the reaction mixture using filtration,centrifugation, screening, or a similar technique.

These separation techniques take advantage of the phase differencebetween the immobilized catalyst and the reaction mixture, therebyavoiding contamination problems. The methods are particularly useful forpharma applications where contamination has negative effects for endusers (i.e., patients). The efficient separation techniques of theinvention can also reduce some of the costs associated with the moredifficult separation techniques used to remove homogeneous catalystsfrom reaction products. Many of the separation techniques of theinvention make it possible to reuse the catalyst in a subsequentreaction. Recycling catalyst can provide an economic advantage sincemany of the catalysts of the invention include precious metals and/ororganic ligands that are expensive to dispose of.

V. EXAMPLES

The following examples provide formulas for making and using immobilizedorganometallic complexes according to certain embodiment of theinvention.

Example 1 Preparation of Immobilized Catalyst Complex

Example 1 provides a method for preparing an immobilized catalyst on aninorganic oxide support. First, an extender agent was bonded to thesurface of SiO₂. 5.38 g of (3-aminopropyl) trimethoxysilane was added toa suspension of 20 g SiO₂ in 100 ml toluene. The suspension was refluxedfor 12 hr under Ar atmosphere. After filtration, the solid was washed by20 ml toluene for three times and then dried. 10 g of the extendermodified SiO₂ solid was added to a solution of 2.52 g adipoyl chloridein 50 ml toluene. The suspension was heated to reflux with stirring for12 hr and then followed by filtration and dryness. The extender andtethering agent modified SiO₂ was ready to use for immobilizing s-BINAP.

Next, s-BINAP was immobilized on the tether-modified SiO₂. 10 g of thetether-modified SiO₂ was stirred in 40 ml solution of 1.0 M AlCl₃ innitrobenzene under Ar atmosphere. 0.45 g s-BINAP in 10 ml nitrobenzenewas added using a syringe. This suspension was heated to 120° C. for 12hr. Thereafter the solid was filtered out and washed 3 times by freshnitrobenzene and then 2 times by toluene to yield an immobilized ligandintermediate.

Finally, the catalyst complex was prepared using the immobilized s-BINAPligand. To prepare immobilized Ru(s-BINAP)Cl₂ catalyst, 10 g of theligand immobilized ligand intermediate was added to 50 ml toluene.Thereafter, 0.248 g dichloro(1.5-cyclooctadiene)ruthenium(II) polymerwas added. The suspension was heated to reflux for 12 hr under Aratmosphere. After cooling down, the solid was filtered out and washedseveral times using DMF until wash was colorless. The immobilized Ru(s-BINAP)Cl₂ was ready to use after drying in a vacuum.

Example 2 Preparation of Immobilized Catalyst Complex

Example 2 describes the preparation of Ru(s-BINAP)Cl₂ using a similarprocedure as in Example 1 except that organometallic complex is formedprior to reacting the tethering agent with the BINAP ligand. 10 g of thetether-modified SiO₂ from Example 1 and 0.6 g of Ru(s-BINAP)Cl₂ wereadded to 50 ml solution of 1.0M AlCl₃ in nitrobenzene. The suspensionwas heated to reflux for 12 hr under Ar atmosphere. After cooling down,the solid was filtered out and washed several times by DMF and tolueneuntil the wash was colorless. The immobilized Ru(s-BINAP)Cl₂ was readyto use after drying in a vacuum.

Example 3 Preparation of Immobilized Catalyst Complex

Example 3 describes the preparation of Ru(PPh₃)₃Cl₂ immobilized onalumina. 10 g of Al₂O₃ (gamma, basic surface) and 4.0 g of polyacrylicacid were added to 30 ml benzene. Then a few drops of trifluoroaceticacid were added. The mixture was heated to 80° C. for 3-4 hr. Afterfiltration, the solid was washed by EtOH and water and then added to thesolution of 1.08 g NaOH in 50 ml H₂O and dried. The surface-modifiedAl₂O₃ support was ready for catalyst immobilization.

10 g of surface-modified Al₂O₃ was added to 40 ml toluene. The solutionof 0.417 g Ru(PPh₃)₃Cl₂ in 10 ml toluene was added through a cannula.The suspension was stirred under N₂ atmosphere for 12 hr. After that thecolor in the solvent disappeared the Al₂O₃ particles turned yellow.After filtration, washing with toluene and drying, the immobilizedRu(PPh₃)₃Cl₂ was available for use. The content of Ru, 0.41 wt %, wasdetermined by atomic absorption spectrum.

Example 4 Preparation of Immobilized Catalyst Complex

Example 4 describes a method for preparing Rh(PPh₃)₃Cl on alumina. themethod of Example 4 was carried identical to the method of Example 3,except that Rh(PPh₃)₃Cl was used instead of Ru(PPh₃)₃Cl₂.

Example 5 Preparation of Immobilized Catalyst Complex

Example 5 describes a method of making Ru(s-BINAP)Cl₂ immobilized onalumina. 5 g of the surface-modified Al₂O₃ available from the procedurein Example 3, 0.1 g Ru(s-BINAP)Cl₂, and 1.0 equiv s-BINAP were added to40 ml methanol under argon atmosphere. The suspension was stirred atroom temperature until the methanol solution turned colorless. Afterfiltration, washing with methanol, and drying, the immobilizedRu(s-BINAP)Cl₂ chiral catalyst was ready for use.

Example 6 Preparation of Immobilized Catalyst Complex

Example 6 describes a method for preparing Ru(s-BINAP)Cl₂ on alumina. 10g of Al₂O₃ (gamma, basic surface) and 0.3 g of 6-amino-1-hexanol wereadded to 30 ml THF. Then a few drops of trifluoroacetic acid were added.The mixture was heated to 80° C. for 8 hr. After filtration, the solidwas washed with EtOH and water and then added to the solution of 1.08 gNaOH in 50 ml H₂O. The mixture was stirred for 2 hr at room temperature,followed by filtration, washing by acetone, and drying. Thesurface-modified Al₂O₃ support was ready for catalyst immobilization.

5 g of the surface-modified Al₂O₃ was added to 40 ml methanol. Asolution of 0.1 g Ru(s-BINAP)Cl₂ and 1.0 equiv. s-BINAP in 10 mlmethanol were added through a cannula. The suspension was stirred underargon atmosphere for 12 hr. After filtration, washing with methanol, anddrying, the immobilized Ru(s-BINAP)Cl₂ was ready for use.

Example 7 Asymmetric Hydrogenation of Methyl Acetoacetate

Example 7 describes a method for asymmetrically hydrogenating methylacetoacetate to form S-(+)-methl-3-hydroxyl-buterate. 4.0 g SiO₂immobilized Ru (s-BINAP)Cl₂ catalyst manufactured using the method ofExample 1 and 3.32 g methyl acetoacetate were placed in 300 ml stainlesssteel autoclave equipped with a mechanically stirring blade, a pressuregauge, and a gas inlet tube attached to a hydrogen source. Air presentin the autoclave was replaced by nitrogen. 100 ml methanol was added tothe autoclave under a stream of nitrogen. The mixture was degassed bythree vacuum-filling with nitrogen cycles. Thereafter, the autoclave wascharged with about 30 psi nitrogen and then heated to 100° C. When thetemperature stabilized, the vessel was pressurized to 1060 psi withhydrogen. The reaction mixture was vigorously stirred for 2 hr at 100°C. The conversion of methyl acetoacetate toS-(+)-methl-3-hydroxyl-buterate was determined by HPLC (column, AGP150×40 mm; eluent, 10:90 2-propanol-H₂O with PH 5.9; temp, 27.8° C.;flow rate, 0.3 ml/min. The t_(R) of S-(+)-methyl-3-hydroxyl-butyrate was5.40 min (84.23%), the tR of R-isomer, 4.71 min.(<0.5%), and the tR ofmethyl acetoacetate was 4.76 min. (15.77%). The conversion was 84.23%with >99% enantiomeric excess.

Example 8 Asymmetric Hydrogenation of Methyl Acetoacetate

Example 8 describes a method for asymmetrically hydrogenating methylacetoacetate to form S-(+)-methl-3-hydroxyl-buterate using a recycledcatalyst. Catalyst used in the method of Example 7 was obtained byfiltration and used in a second run according to the method of Example7. The conversion determined by HPLC was 96.45% with >99% enantiomericexcess.

Example 9 Asymmetric Hydrogenation of Methyl Acetoacetate

Example 9 describes a method for asymmetrically hydrogenating methylacetoacetate to form S-(+)-methl-3-hydroxyl-buterate. The procedure wascarried out similar to the procedure describe in Example 7 except thatthe immobilized catalyst of Example 2 was used rather than the catalystfrom Example 1. The reaction was carried out for 4 hr using 4.0 g of theimmobilized Ru(s-BINAP)Cl₂ catalyst from Example 2. The conversiondetermined by HPLC was 83.39% with >99% enantiomeric excess.

Example 10 Asymmetric Hydrogenation of Methyl Acetoacetate

Example 10 describes a method for asymmetrically hydrogenating methylacetoacetate to form S-(+)-methl-3-hydroxyl-buterate using a recycledcatalyst. Catalyst used in the method of Example 9 was obtained byfiltration and used in a second run, and then in a subsequent third run,and subsequent fourth run. All were subsequent runs were performed byfiltering the catalyst from the prior reaction and reusing the catalystaccording to the method of Example 9, except that the reaction time was6 hr. The product was analyzed by HPLC and determined to be 95.86%conversion and 99% ee for the second run, 95.98% conversion and 99% eefor the third run, and 95.59% conversion and 99% ee for the forth run.

As shown in the foregoing examples, high conversion and high selectivitycan be achieved in reactions using the immobilized catalyst of thepresent invention. The immobilized catalysts are readily recoverable foruse in subsequent reactions. Surprisingly, recycled catalyst even showedimproved conversion compared to freshly prepared immobilized catalyst.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A method for immobilizing an aryl-containing organic ligand,comprising: combining together the following in a single reactionmedium: an organic ligand comprising at least one aryl group orfunctionalized aryl group; a functionalized support material having aplurality of available functional groups; and a tethering agent havingan anchoring functional group capable of bonding with the functionalizedsupport material and a bonding functional group that is capable ofbonding to the aryl group or functionalized aryl group, wherein theanchoring functional group is selected so as to be capable of reactingwith the functionalized support material in the same reaction medium asa reaction medium used to react the bonding functional group with thearyl group or functionalized aryl group of the organic ligand; and inthe single reaction medium, (i) reacting the bonding functional group ofthe tethering agent with the aryl group or functionalized aryl group ofthe organic ligand and (ii) reacting the anchoring functional group ofthe tethering agent with an available functional group of the supportmaterial, so as to yield an aryl-containing organic ligand immobilizedon the support material.
 2. A method as in claim 1, wherein the bondingfunctional group of the tethering agent comprises an acyl halide and thereaction of the bonding functional group comprises aFreidel-Crafts-acylation reaction.
 3. A method as in claim 1, whereinthe bonding functional group and the anchoring functional group of thetethering agent are provided by at least one of a dialkyl halide or adiacyl halide.
 4. A method as in claim 1, where the bonding functionalgroup of the tethering agent reacts with the aromatic ring of the arylgroup.
 5. A method as in claim 1, wherein the reaction of the bondingfunctional group and the reaction of the anchoring functional groupoccur simultaneously.
 6. A method as in claim 1, wherein the organicligand is a ligand that can be used to manufacture a chiral catalyst. 7.A method as in claim 1, wherein the tethering agent is selected from thegroup consisting of polyfunctional carboxylic acids, polyacids withfunctionality of three or greater, polymeric acids, hydroxy acids, alkylhalides, acyl halides, nitriles, pyridines and derivatives thereof.
 8. Amethod as in claim 1, wherein the tethering agent is selected from thegroup consisting of oxalic acid, malonic acid, succinic acid, glutaricacid, adipic acid, maleic acid, fumaric acid, phthalic acid, isophthalicacid, terephthalic acid, citric acid polyacrylic acid, glycolic acid,salicylic acid, hydroxy propanoic acid, compounds of the general formulaHO(CH_(x))_(n)COCl, compounds of the general formulaHOOC(CH_(x))_(n)COCl, compounds of the general formulaClOC(CH_(x))_(n)COCl, hydroxyacetonitrile, 3-hydroxyproprionitrile,2-hydroxyisobutyronitrile, carboxyacetonitrile, 2-hydroxymethylpyridine,picolinic acid (2-pyridine carboxylic acid), nicotinic acid (3-pyridinecarboxylic acid), quinolinic acid (2,3-pyridine dicarboxylic acid), andcombinations thereof.
 9. A method as in claim 1, wherein the aryl groupis selected from the group consisting of benzene, indene, naphthalene,fluorine, chrysene, phenanthrene, anthracene, triphenylene, and aryl-Oand aryl-N derivatives thereof, with the proviso that the groups do notinclude electron withdrawing substituents.
 10. A method as in claim 1,wherein the organic ligand is selected from the group consisting ofBINAP, BICHEP, DIPAMP, BINAPHANE, BINAPO, BDPAB, and alkyl, alkyl-O, oralkyl-N derivatives thereof, with the proviso that the derivatives donot have electron withdrawing group substituents.
 11. A method as inclaim 1, wherein the support material further comprises extender groupsand the available functional groups of the support material are providedby the extender groups.
 12. A method as in claim 1, after the tetheringagent is bonded to the organic ligand the method further comprisingcomplexing the organic ligand with a metal atom.
 13. A method as inclaim 1, further comprising complexing the organic ligand with a metalatom prior to bonding the organic ligand to the tethering agent.
 14. Amethod as in claim 1, wherein the tethering agent provides a separationof at least 3 atoms between the support material and the organic ligand.15. A method as in claim 1, wherein the tethering agent provides aseparation of at least 8 atoms between the support material and theorganic ligand.
 16. A method as in claim 1, wherein the support materialis selected from the group consisting of alumina, silica, zirconia,titania, ceria, natural and synthetic zeolites, clay, reverse phasesilica, and combinations thereof.
 17. A method as in claim 1, whereinthe support material is selected from the group consisting carbon black,activated carbon, graphite, polymers, resins.
 18. A method forimmobilizing an aryl-containing organic ligand, comprising: providing anorganic ligand comprising at least one aryl group; providing afunctionalized support material having a plurality of availablefunctional groups; providing a tethering agent comprising a plurality ofmolecules, each having (i) a bonding functional group comprising aleaving group, and (ii) an anchoring functional group capable of bondingwith the functionalized support material; reacting the tethering agentwith the organic ligand in an alkylation reaction or an acylationreaction so as to form a carbon-carbon bond between the tethering agentand the aryl group of the organic ligand, wherein the anchoringfunctional group comprises at least one of an acyl halide or an alkylhalide; and reacting the anchoring functional group of the tetheringagent with an available functional group of the functionalized supportmaterial.
 19. A method as in claim 18, wherein the support materialfurther comprises an extender group and the extender group provides theavailable functional group.
 20. A method as in claim 18, wherein theavailable functional group of the support material comprises an amine oran aromatic group.
 21. A method as in claim 18, wherein the reactions ofthe tethering agent with the support material and the tethering agentwith the organic ligand are carried out in a single reaction step.